Four and one-half-year follow-up of the effectiveness of diphtheria-tetanus toxoids-acellular pertussis/Haemophilus influenzae type b and diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus/H. influenzae type b combination vaccines in Germany

BACKGROUND: Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was observed in the United Kingdom, which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis (DTaP) Hib vaccines. A study in Germany based on approximately 2 years of follow-up, estimated vaccine effectiveness (VE) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high. OBJECTIVES: To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake. SUBJECTS AND METHODS: Cases with confirmed systemic Hib infections in children born between June 1, 1996 and December 31, 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002. A representative subcohort of 667 children born in the same time frame was randomly sampled in a nationwide vaccine coverage survey. VE was determined with a case-cohort approach of Cox regression with time-dependent covariates. RESULTS: Thirty-six cases of Hib disease were reported. Of these, 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated. Of the 10 vaccinated cases, 4 had received an incomplete primary series (1-2 doses), and 6 had received the full primary series (3 doses), 3 of whom also received the booster dose. VE of combination vaccines against invasive Hib infection was 89.6% [95% confidence interval (CI), 67.0-96.7] for an incomplete primary series, 96.7% (95% CI 87.7-99.1) for a full primary series and 98.5% (95% CI 94.5-99.6) for a booster dose (irrespective of priming). CONCLUSION: Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

AIMS: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. METHODS: Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. RESULTS: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). CONCLUSIONS: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure

Aims: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Methods: Unmatched case-control study in the UK and Eire 1992–2001 and Victoria, Australia 1988–1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Results: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 µg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 µg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 µg/ml (2.78 to 5.15); unvaccinated GMC 1.48 µg/ml (0.90 to 2.21); p = 0.003). Conclusions: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladeshi children: a case-control study

BACKGROUND: Few Asian countries have introduced Haemophilus influenzae type b (Hib) conjugate vaccine because of its cost and uncertainty regarding disease burden. METHODS: To estimate the effectiveness of Hib conjugate vaccine in preventing pneumonia and meningitis in children age <2 years, an incident case-control study was conducted in a birth cohort of about 68,000 infants in Dhaka city, Bangladesh. DPT vaccine was systematically replaced by a combined Hib-DPT vaccine in selected immunization centers of the study area. Four matched community- and 2 hospital-controls were randomly selected for each confirmed case of pneumonia and meningitis from the study area. RESULTS: About 35% of the infants received each of the 3 doses of Hib-DPT vaccine. There were 2679 children who had a chest roentgenogram. For 475 children, a radiologist and a pediatrician independently identified substantial alveolar consolidation. Following at least 2 doses of Hib vaccine, the preventable fractions [95% confidence intervals (CI)] using community and hospital controls were 17% (-10% to 38%) and 35% (13% to 52%) respectively. Of these 475 cases, 2 radiologists with the World Health Organization concurred with the findings for 343 patients, yielding preventable fractions of 34% (6% to 53%) and 44% (20% to 61%). Fifteen confirmed Hib meningitis cases were identified; the preventable fractions (95% CI) using community and hospital controls, respectively, were 89% (28% to 100%) and 93% (53% to 100%). CONCLUSIONS: The study documented that significant fractions of pneumonia and meningitis in Bangladeshi children age <2 years can be prevented by the Hib conjugate vaccine.     

Experience with the prevention of invasive Haemophilus influenzae type b disease by vaccination in Alaska: the impact of persistent oropharyngeal carriage

OBJECTIVES: To report the epidemiology of invasive Haemophilus influenzae type b (Hib) disease in high-risk Alaska Native infants before and after universal infant Hib vaccination and evaluate an increase in invasive Hib disease in 1996 after changing Hib vaccine type. STUDY DESIGN: Statewide laboratory surveillance for invasive Hib disease has been conducted since 1980. Three cross-sectional Hib carriage studies were conducted in 1997 and 1998. RESULTS: The invasive Hib disease rate in Alaska Natives decreased from 332 cases per 100,000 children <5 years old in 1980-1991 to 17:100,000 in 1992-1995 but increased primarily in rural areas to 57.9:100,000 after a switch in Hib vaccine types. Carriage studies in 5 rural Alaska Native villages showed oropharyngeal Hib carriage as high as 9.3% in children aged 1 to 5 years; in contrast, carriage in urban Alaska Native children was <1%. CONCLUSIONS: Although Hib disease has decreased in Alaska, the rate of Hib disease and carriage in rural Alaska Natives did not decrease to the same extent as in non-Natives and urban Alaska Natives. Use of polyribosylribitol phosphate-outer-membrane protein conjugate vaccine for the first vaccine dose is critical to disease control in this population with continued transmission in infants <6 months of age. The ability to eliminate Hib carriage and disease may be affected by population characteristics, vaccination coverage, and Hib vaccine type used. This may pose a challenge to global elimination of Hib.     

Invasive disease due to Haemophilus influenzae type b during the first six years of general vaccination of Swedish children

Since 1992-93 vaccination against Haemophilus influenzae type b (Hib) has been included in the general Swedish childhood vaccination programme. The aim of the present study is to describe the epidemiology, identify and describe vaccine failures and calculate vaccine effectiveness during the first 6 y after introduction of vaccination against Hib. Laboratory reports of blood and cerebrospinal isolates to the Swedish Institute for Infectious Disease Control were used as the source for identifying the patients. Additional information was subsequently obtained from physicians and parents of children who had developed the disease during the study period. Vaccine failures were identified and vaccine effectiveness calculated. During the study period, 152 cases of invasive H. influenzae were identified in the age group 0-14 y. During the 6-y period, 6 true vaccine failures, 6 apparent vaccine failures and 1 possible vaccine failure were found in nearly two million vaccinated child-years. The effectiveness of the Hib vaccination in the birth cohort of children 1993 to 1997 in Sweden was calculated to be 96.1% (95% confidence interval 94.2-97.5). The study supports earlier studies from several countries that conjugated Hib vaccination introduced in general childhood vaccination programs is effective and substantially decreases suffering from invasive Hib diseases.     

Haemophilus influenzae type b conjugate vaccine diluted tenfold in diphtheria-tetanus-whole cell pertussis vaccine: a randomized trial

BACKGROUND: Despite their proven efficacy Haemophilus influenzae type b (Hib) conjugate vaccines are not given to most children in the developing world in the face of an estimated global Hib disease burden of nearly 2 million cases per annum. A major barrier to the introduction of the vaccine would be overcome by diluting the vaccine 10-fold in diphtheria-tetanus-whole cell pertussis (DTP). We report a randomized trial comparing the use of Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full Hib dose. METHODS: We randomized 168 infants to receive either the full dose Hib polysaccharide-tetanus toxoid conjugate (PRP-T) vaccine or a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial. Infants were vaccinated at 6, 10 and 14 weeks of age and received a full dose as a test of immunologic memory at 9 months of age. Sera were collected at each visit and at 1 week after the booster dose. Serum anti-capsular PRP antibody concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: After the primary vaccination series, 95% of infants in the full dose arm and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody concentrations of > or = 1.0 microg/ml. Infants receiving the diluted vaccine had significantly higher titers of anti-PRP antibody in response to the booster dose (151.36 microg/ml vs. 68.55 microg/ml, P = 0.009). CONCLUSIONS: The 1/10 dose of PRP-T was as immunogenic and safe as the full dose. The technique of diluting a single dose of PRP-T in a 10-dose DTP vial could potentially allow the widespread introduction of Hib vaccine in resource-poor countries currently unable to afford full dose Hib conjugate vaccine.     

Vaccine-preventable haemophilus influenza type B disease burden and cost-effectiveness of infant vaccination in Indonesia

BACKGROUND: Most of Asia, including Indonesia, does not use Haemophilus influenzae type b (Hib) conjugate vaccines. We estimated total vaccine-preventable disease burden and the cost-effectiveness of Hib conjugate vaccine in Indonesia. METHODS: Hib pneumonia and meningitis incidences for children with access to health care were derived from a randomized vaccine probe study on Lombok Island, Indonesia during 1998-2002. Incidences were adjusted for limited access to care. Health system and patient out-of-pocket treatment cost data were collected concurrent with the probe study. For Hib vaccine in monovalent and combined (with DTP-HepB) presentations, we used 2007 UNICEF vaccine prices of US$3.30 and $3.75 per dose. RESULTS: For the 2007 Indonesian birth cohort, Hib vaccine would prevent meningitis in 1 of every 179 children, pneumonia in 1 of every 18 children, and 4.9% of mortality among those younger than 5 years. The total incremental societal costs of introducing Hib vaccine in monovalent and pentavalent presentations were, respectively, US$11.74 and $8.93 per child vaccinated. Annual discounted treatment costs averted amounted to 20% of pentavalent vaccine costs. For the pentavalent vaccine, the incremental costs per discounted death and disability adjusted life-year averted amounted to US$3102 and $74, respectively, versus $4438 and $102 for monovalent vaccine. CONCLUSIONS: Routine infant Hib vaccination would prevent a large burden of pediatric illness and death in Indonesia. Even without external funding support, Hib vaccine will be a highly cost-effective intervention in either a monovalent or pentavalent presentation based on commonly used benchmarks.     

Non-type b Haemophilus influenzae disease: clinical and epidemiologic characteristics in the Haemophilus influenzae type b vaccine era

BACKGROUND: As a result of the decline in Haemophilus influenzae type b (Hib) disease caused by the widespread use of conjugate vaccines, non-type b H. influenzae will become a more important cause of H. influenzae (Hi) disease. Characterization of the clinical and epidemiologic features of non-b Hi disease is needed in the Hib vaccine era. METHODS: A prospective active surveillance study of invasive Hi disease involving pediatricians in the United Kingdom and Republic of Ireland. For the first phase of the study (October 1, 1992, to October 31, 1995) pediatricians were asked to report any child who had invasive Hi disease and who had received Hib conjugate vaccine. For the second phase of the study (November 1, 1995. To December 31, 1998) pediatricians were asked to report any child with invasive Hi disease regardless of vaccination status. RESULTS: During the study period 102 cases of invasive non-type b Hi disease and 106 cases of invasive Hib disease were reported in children who had been fully vaccinated against Hib. Children with non-type b disease were younger (16 vs. 22 months of age, P = 0.08), less likely to have meningitis and epiglottitis (P < or = 0.001) and more likely to have pneumonia and bacteremia (P < or = 0.001) than children with type b disease. For the last 2 years of the study invasive Hi disease occurring in a fully vaccinated child was more likely to be caused by a non-b strain than by a type b strain (58 vs. 38). In 1998 the incidence of non type-b Hi disease in all children <5 years of age in the UK was 1.3/100,000 as compared with an incidence of Hib disease of 0.6/100,000. The majority (88%) of non-b strains isolated in children were nontypable strains. CONCLUSIONS: Non-b Hi is a rare cause of disease in children, but in the Hib vaccine era it has become more common than type b as a cause of Hi disease in fully vaccinated children.     

Haemophilus influenzae type b antibodies in vaccinated and non-vaccinated children

Background: Invasive Haemophilus influenzae type b (Hib) infection has a high morbidity among young children, but the burden of disease and rate of Hib are different in different regions. The aim of the present study was to investigate the levels of Hib antibodies and the oropharyngeal Hib prevalence in young children.
Methods: One hundred-fifty nine healthy children aged 19–36 months of age were included in this cross-sectional study. Anti-polyribosylribitol phosphate (anti-PRP) antibody concentrations were measured using commercially available enzyme-linked immunosorbent assay (ELISA), and serotyping of isolated Hib strains was conducted by slide agglutination with specific antisera.
Results: Of the study participants, 57 (35.8%) were fully vaccinated (group 1A); 17 (10.7%) were incompletely vaccinated (group 1B), and 85 (53.5%) were non-vaccinated (group 2). Geometric mean titer (GMT) of anti-PRP antibody was 3.8 μg/mL, 2.2 μg/mL and 0.49 μg/mL in group 1A, group 1B and group 2, respectively. While all children in group 1 ( n  = 74) had seroprotective antibody concentrations (≥0.15 μg /mL), of the children in group 2 ( n  = 85) 31.8% did not have seroprotective anti-PRP levels ( P  < 0.0001). A total of 68.2% in group 2 had natural immunity. Nineteen children (33.3%) in group 1, and 46 (54.1%) in group 2 had oropharyngeal Hib colonization ( P  = 0.0004).
Conclusions: Hib conjugate vaccine is immunogenic and reduces Hib colonization. Each country should investigate the burden of Hib disease and the natural immunity in young children, and should determine antigenic dose, number of doses administered and dose intervals before deciding whether to introduce Hib conjugate vaccine in routine immunization programs.     

Efficacy of Haemophilus influenzae type b vaccines in Massachusetts children 18 to 59 months of age.

Since 1987 Haemophilus influenzae b (Hib) conjugate vaccines have been licensed for use in children ages 18 months and older. Before licensure there were no clinical trials of a single dose of any conjugate vaccine in children ages 18 months or older. To fulfill this need we performed an age- and residence-matched case-control study of the efficacy of Hib vaccines. In our study population the protective efficacy (PE) of Hib-diphtheria toxoid conjugate vaccine was 88% (95% confidence interval, 45 to 98%). No vaccine failures were observed with Hib oligosaccharide CRM197 diphtheria protein conjugate vaccine, but usage was not sufficient to establish efficacy: PE = 100% (95% confidence interval, -37 to 100%). The protective efficacy of Hib capsular polysaccharide vaccine was 18% (95% confidence interval -487 to 89%). We conclude that for children ages 18 to 60 months a single dose of the Hib conjugate vaccine, PRP-D, is protective against invasive Hib infections. Consistent with most studies Hib polysaccharide vaccine provided suboptimal protection.     

Prevention of pneumococcal disease in children. Pneumococcal conjugate vaccines: their use globally could have a major impact on public health

Pneumococcal disease is a major cause of morbidity and mortality in infants and young children worldwide. New pneumococcal conjugate vaccines include 7 to 11 serotypes, which are the most common cause of paediatric disease in most parts of the world. The efficacy of a 7-valent conjugate vaccine was 97.4% (95% CI, 82.7-99.9) against invasive pneumococcal disease, and 57% (95% CI, 44-67) against otitis media, caused by vaccine serotypes. Evidence shows that the vaccine has the potential to prevent pneumonia. Pneumococcal conjugate vaccination has also been shown to reduce nasopharyngeal carriage of vaccine serotypes (particularly serotypes associated with antibiotic resistance). Thus widespread use of pneumococcal conjugate vaccine could substantially reduce the burden of invasive disease and would have the potential to control the global spread of antibiotic resistance in pneumococci. Conclusion: It is important that these highly effective vaccines should be made available to children in the developing countries.     

Immunization with oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine on a large health maintenance organization population: extended follow-up and impact on Haemophilus influenzae disease epidemiology. The Kaiser Permanente Pediatric Vaccine Study Group.

Between February, 1988, and June, 1990, the safety, immunogenicity and efficacy of the HbOC (oligosaccharide conjugate Haemophilus influenza type b) vaccine was evaluated in a prelicensure trial performed in a study population of 61,080 children within the Northern California Kaiser Permanente Medical Care Program. In this evaluation the HbOC vaccine was found to be safe, immunogenic and efficacious in infancy. Since licensure an estimated 162,000 additional doses of HbOC vaccine have been given to 75,000 additional children. In addition to reporting on extended follow-up of this population, this publication reports on the impact of immunizing a high proportion of the Northern California Kaiser Permanente Medical Care Program population in infancy and early childhood on the epidemiology of invasive disease caused by H. influenzae type b (Hib) and invasive disease caused by non-type b H. influenzae. As of January 31, 1992, six cases of Hib invasive disease have been identified in vaccinated children. Of these five occurred in children who had received only one dose of vaccine in infancy. One case of Hib meningitis occurred in a 3 1/2-year-old child who had received doses of HbOC at 2, 4 and 6 months of age but no further doses of any Hib vaccines. During 1991 a total of three cases of invasive disease caused by Hib were observed in children younger than 18 months of age within the Northern California Kaiser Permanente Medical Care Program. This represents a 94% reduction in disease incidence in this age group from that observed in the years 1984 to 1987.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunogenicity of Haemophilus b conjugate vaccine (meningococcal protein conjugate) in children with prior invasive Haemophilus influenzae type b disease

Children younger than 2 years of age with previous invasive Haemophilus influenzae (Hib) type b disease may not develop protective antibodies to antigens of Hib and may be at risk of developing a second episode of Hib disease. Twenty-three children with prior Hib disease were immunized with Haemophilus b conjugate vaccine (meningococcal protein conjugate). Children 12 to 24 months of age were given one dose of vaccine and children younger than 12 months of age were given 2 doses 2 months apart. Antibody to the polysaccharide capsule of Hib (PRP) was measured by radioimmunoassay. Eighteen children had preimmunization serum antibody concentrations less than 0.150 micrograms/ml. All 18 children responded with greater than 0.150 micrograms/ml of antibody after a single dose of vaccine. Only 1 of the 23 children had a preimmunization serum antibody concentration greater than 1.000 micrograms/ml. Seventeen children ultimately responded with greater than 1.000 micrograms/ml of antibody (P less than 0.0001), concentrations of antibody thought to correlate with protection. Haemophilus b conjugate vaccine (meningococcal protein conjugate) is immunogenic in children with invasive Hib disease. Children younger than 2 years of age with invasive Hib disease should be subsequently immunized with a Hib conjugate vaccine.     

Burden of invasive disease caused by Haemophilus influenzae type b in Bamako, Mali: impetus for routine infant immunization with conjugate vaccine

BACKGROUND: Population-based, bacteriologically confirmed disease burden data aid decision makers in African countries pondering whether to introduce Haemophilus influenzae type b (Hib) immunization for infants. METHODS: A bacteriology laboratory was established in Hopital Gabriel Toure, serving Bamako, Mali. Children age 0-15 years with fever > or =39 degrees C or syndromes compatible with invasive bacterial disease (meningitis, etc.) were eligible. From 2 to 5 mL of blood or relevant body fluid were inoculated into Bactec Ped Plus/F medium for automated culture; body fluids were also inoculated directly onto solid media. Hib was confirmed by standard microbiologic techniques and antibiograms generated by disk diffusion. RESULTS: From June 1, 2002 to May 31, 2004, 3592 (87.8%) of 4092 children admitted to Hopital Gabriel Toure with high fever or suspected invasive bacterial disease were cultured, including 1745 who were 0-11 months old, 1132 who were 1-4 years old and 715 who were 5-15 years old. Hib was isolated from 207 Bamako children, 81 from blood alone and 124 from cerebrospinal fluid (with or without positive blood culture). Of 207 cases 204 (98.5%) occurred in children younger than age 5 years (annual incidence, 45.2/10) and 159 (77%) in infants age 0-11 months (annual incidence, 158.4/10). Peak incidence (370.0 cases/10) and 12 of 21 Hib deaths occurred in 6- to 7-month-olds. Of the Hib isolates, 11.1% were resistant to ampicillin, 32% to chloramphenicol and 0.5% to ceftriaxone. CONCLUSIONS: The substantial burden of invasive Hib disease documented in Bamako has prompted the Malian government to introduce routine infant immunization with Hib conjugate.     

Efficacy and safety of a Haemophilus influenzae type b capsular polysaccharide-tetanus protein conjugate vaccine.

A polyribosylribitol phosphate (polysaccharide)-tetanus protein conjugate vaccine (PRP-T) against Haemophilus influenzae type b (Hib) was evaluated for safety and efficacy after vaccination of more than 100,000 infants. No major side effects were attributed to the vaccine. Immunogenicity studies showed an antibody response in 70% to 100% of infants after two doses, and in 98% to 100% of infants after three doses, within the first 6 months of life. Antibodies persisted in 90% of recipients, in whom significant anamnestic responses developed after a booster dose at 18 months of age. In comparison with other available Hib vaccines, PRP-T induces equal or higher mean titers after three doses. Although licensure of other vaccines interrupted controlled efficacy trials, up to that point five cases of Hib disease in those trials had occurred in placebo recipients, and no Hib disease has been reported in the more than 100,000 vaccinated infants who have received more than one dose of PRP-T. Thus PRP-T combined immunogenicity early in life with induction of immunologic memory.     

Immunogenicity of Haemophilus influenzae type b polysaccharide-outer membrane protein conjugate vaccine in patients who acquired Haemophilus disease despite previous vaccination with type b polysaccharide vaccine

To investigate the basis of the immune defect in children who acquire invasive Haemophilus disease despite previous vaccination with Haemophilus influenzae type b (Hib) polysaccharide vaccine, we determined the ability of vaccine failure patients with low levels of serum anticapsular antibody (less than 1 microgram/ml) to respond to reimmunization. Thirty-four patients, ranging in age from 27 to 61 months, were vaccinated with either Hib polysaccharide (n = 20) or Hib polysaccharide-outer membrane protein conjugate vaccine (n = 14). All but three of the children had normal serum concentrations of immunoglobulins, including IgG2. The geometric mean serum anticapsular antibody concentration of the group given polysaccharide vaccine increased from 0.27 microgram/ml before vaccination to 0.65 microgram/ml 1 month later (p less than 0.05), but the magnitude of the response was nearly 10-fold less than that of 31 age-matched control children given polysaccharide vaccine (6.3 micrograms/ml, p less than 0.001). In contrast, all 14 patients with vaccine failure who were given conjugate vaccine showed increases of fivefold or more in serum anticapsular antibody (geometric means 0.35 and 12.8 micrograms/ml, respectively; p less than 0.001). All patients with vaccine failure who did not respond to polysaccharide vaccine were subsequently given conjugate vaccine, and all had high antibody responses. Most patients tested showed increases in complement-mediated serum bactericidal activity. These data suggest that immunization with conjugate vaccine confers protection against Hib disease to children who, because of genetic or other reasons, cannot respond to the unconjugated form of the polysaccharide vaccine.     

Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group

OBJECTIVE: To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media. METHODS: The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37,868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate. The primary study outcome was invasive disease caused by vaccine serotype. Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement. In addition the serotype-specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears. RESULTS: In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100%. Blinded case ascertainment was continued until April, 1999. As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent-to-treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%). There was no evidence of any increase of disease caused by nonvaccine serotypes. Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype-specific effectiveness was 66.7%. CONCLUSION: This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.     

Lower respiratory tract infections associated with influenza A and B viruses in an area with a high prevalence of pediatric human immunodeficiency type 1 infection

BACKGROUND: Despite the high burden of pediatric HIV-1 infection in developing countries, there are few data on the clinical course of influenza virus-associated lower respiratory tract infection (LRTI) in these children. OBJECTIVE: To define and compare the clinical course of HIV-1-infected and -uninfected African children hospitalized with influenza virus associated severe LRTI. METHODS: Children with severe LRTI were prospectively recruited between March, 1997, and March, 1999, as part of a broader study evaluating the etiology and outcome of this condition in hospitalized HIV-1-infected and -uninfected children. The results of children in whom influenza A or B virus was identified by immunofluorescent antibody staining after shell vial culture are reported. Viruses isolated were typed by hemagglutination inhibition assays. RESULTS: Twenty-five (21.6%) of the 116 children hospitalized with severe LRTI in whom influenza A or B virus was identified were HIV-1-infected. HIV-1-infected children were older than uninfected children (mean age +/- SD 17.4 +/- 10.8 months vs. 10.2 +/- 8.9 months; P = 0.002). HIV-1-infected children were more likely to have an underlying medical illness (in addition to HIV-1 infection) predisposing them to more severe LRTI (32.0% vs. 13.2%; P = 0.03). HIV-infected children were also more likely to have indirect evidence of bacterial coinfection, including chest radiographic evidence of confluent alveolar consolidation (78.9% vs. 35.1%, P = 0.006), and were less likely be wheezing (8.0% vs. 31.9%, P = 0.01). However, there was no difference in the clinical outcome of HIV-1-infected and -uninfected children. The duration of hospitalization [median (range) 5 (2 to 33) days vs. 4 (0 to 21) days, P = 0.08] and the mortality rates (8.0% vs. 2.2%, P = 0.20) were similar between HWV-1-infected and -uninfected children. CONCLUSION: HIV-1-infected children hospitalized with severe LRTI associated with influenza virus have an outcome similar to that of HIV-1-uninfected children even in the absence of antiretroviral or anti-influenza virus treatment.